Tetrahydro-cyclopropa(b)naphthalenes

ABSTRACT

COMPOUNDS ARE PROVIDED HAVING THE STRUCTURE   1-R3,1-R4,1A-R2,6-(R5-O-),7A-R&#39;&#39;,R-1A,2,7,7A-TETRAHYDRO   THESE COMPOUNDS ARE USEFUL AS ANTIPARASTIC AGENTS, ANTIBACTERIAL AGENTS. AND ANTI-INFLAMMATORY AGENTS AS WELL AS SURFACE ACTIVE AGENTS.

United States Patent Oflice.

3,796,766 Patented Mar. 12, 1974 3,796,760 TETRAHYDRO-CYCLOPROPA[b]NAPHTHALENES Venkatachala L. Narayanan, Hightstown, N.J., assignor to E. R. Squibb & Sons, Inc., New York, N.Y. No Drawing. Original application Sept. 18, 1970, Ser. No. 73,668, now Patent No. 3,694,512. Divided and this application May 12, 1972, Ser. No. 252,814

Int. Cl. C07c 43/20 US. Cl. 260-612 R 4 Claims ABSTRACT OF THE DISCLOSURE Compounds are provided having the structure These compounds are useful as antipanasitic agents, antibacterial agents, and anti-inflammatory agents as well as surface active agents.

This is a division of application Ser. No. 73,668, filed Sept. 18, 1970, the parent application has issued as US. Pat. No. 3,694,512.

The present invention relates to tetrahydro-cyclopropa[b]naphthalenes of the structure wherein R is hydrogen, lower alkyl, lower alkoxy, or cycloalkyl; R and R are the same or difierent and can be hydrogen, lower alkyl or lower alkoxy, R and R are the same or diflferent and can be hydrogen, chlorine or bromine, although at least one of R and R is chlorine or bromine; R is hydrogen, lower alkyl, aralkyl or ----(CH ),,,CO;,;R where "1 :1 to 10, and R is hydrogen, lower alkyl, or aralkyl. Furthermore, R can be aminoalkyl having the structure -(CH ),,---NR"R wherein n is 2 to 6, R and R can be the same or different and represent hydrogen, lower alkyl, aralkyl, monocyclic cycloalkyl, monocyclic aryl or hydroxy-lower alkyl and R and R can be taken together with nitrogen to form a 5 to 7 membered monocyclic heterocyclic ring.

The term lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl and the like. The lower alkyl group can include substituents such as aryl.

The term lower alkoxy includes straight and branched chain lower alkyl groups attached to an oxygen.

The term monocyclic aryl as employed herein includes monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, including lower alkyl phenyl, such as tolyl, ethylphenyl, butylphenyl and the like, di(lower alkyl)phenyl (e.g., dimethylphenyl, 3,5-diethylphenyl and the like), halophenyl (e.g., chlorophenyl, bromophenyl, and 2,4,6-trichloropheny1) and nitrophenyl.

The term monocyclic cycloalkyl includes cyclic radicals containing from 3 to 6 ring members (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).

The radicals (CH and -(CH encompass straight chain or branched bivalent lower alkyl groups.

Examples of the basic nitrogen containing radical symbolized by the group include amino, lower alkylamino, e.g., methylamino, ethylamino; di(lower alkyl) amino, e.g., dimethylamino, diethylamino, dipropylamino; (hydroxy lower alkyl) amino, e.g., B hydroxyethylamino; di(hydroxy lower alkyl) amino, e.g., di(hydroxyethyDamino; phenyl(lower alkyl)amino, e.g., benzylamino, and phenethylamino.

As indicated above, the nitrogen may join with the groups represented by R and R to form a 5 to 7 membered monocyclic heterocyclic containing, if desired, an oxygen, sulfur or an additional nitrogen atom (not more than two hetero atoms altogether), that is, the two symbols R", and R represent together tetramethylene, pentamethylene, hexamethylene, oxapentamethylene, oxatetramethylene, azahexamethylene, azapentamethylene, azatetramethylene, thiapentamethylene or thiatetramethylene. The heterocyclic group may also be substituted by one or two groups represented by R, R R and R Illustrative heterocyclic groups include piperidino, e.g.. methylpiperidino, di(lower alkyl)piperidino, e.g. dimethylpiperidino, (lower al-koxy)piperidino, e.g., methoxypiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g., Z-methylpyrrolidino, di(lower alkyl)pyrrolidino, e.g., 2,5- dimethylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., ethoxypyrrolidino, morpholino, (lower alkyl)morpholino, e.g., 3-methylmorpholino or Z-methylmorpholino, di- (lower alkyl)morpholino, e.g., 2,3-dimethylmorpholino, (lower alkoxy)morpholino, e.g., 2- or 3-ethoxymorpholino, thiamorpholino, (lower alkyl)thiamorpholino, e.g., Z-methylthiamorpholino or Z-methylthiamorpholino, di- (lower alkyl)thiamorpholino, e.g., 2,3-diethylthiamorpholino or 2,3-dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., Z-methoxythiamorpholino, piperazino, (lower alkyl)piperazino, e.g., 4-methylpiperazino, Z-methylpiperazino, di(lower alkyl)piperazino, e.g., 2,3-dimethylpiperazino, hydroxy-lower alkylpiperazino, e.g., 4-(2- hydroxyethyl)piperazino, hexamethyl'eneimino and homopiperazino.

Preferred are those compounds wherein R and/or R are chlorine, R and R are hydrogen, R is hydrogen or methyl, and R is hydrogen, methyl or benzyl.

Examples of compounds falling within the present invention include, but are not limited to, the following:

(3) cm (|)H 0 (CH3) 3 C OOH C3117 I O CH:

(IXCHDsNH Cl CzHl (15) CHaCHnOH O (CHflr-N 19 C(CHm-N 20 z)aN Compounds of Formula I can be prepared by the Birch reduction of a naphthol of the structure (II) OH 31 Re I The 5,8-dihydronaphthol is reacted with a halide of the structure wherein R is other than hydrogen and X is Cl, -Br or I, in a molar ratio of naphthol to halide of within the range of from about 0.8:1 to about 1:1, in the presence of a base such as potassium carbonate, sodium ethoxide, sodium hydride or potassium-t-butoxide, at a temperature within the range of from about 65 to about 160 C., to form a compound of the structure which is reacted with a halocarbene of the structure (V :CR R

in a molar ratio of VzVI of within the range of from about 0.1:1 to about 1.5 :1, at a temperature within the range of from about 0 to about 90 C., to form a compound of structure I.

As an alternate approach, a compound of Formula V wherein R is benzyl is first reacted with a halocarbene of structure :CR R under the conditions specified above to give a compound of Formula I where R is benzyl i.e.

The compound of Formula VII is then debenzylated using 5-10% palladium/carbon as catalyst in a solvent like ethyl alcohol to give a compound of Formula I wherein R is H (VIII) OH CH: CH: O

G C 2H5 0 3H CH3 O-[ I 0 I CH3 CH3 V-CHa The halide R X includes halides such as alkyl halides, for example methyl iodide, ethyl chloride, propyl bromide, benzyl chloride, as well as halides of the structure Hal- (ennui-ii o R such as 0 H2)a- 0 sHu Examples of halides of the structure VIH (VIII) Ha1--(CH ),,NR R

suitable for use in preparing compounds of the invention include the following: dimethylaminoethyl chloride, dimethylaminopropyl chloride, methylethylaminomethyl bromide, ethyl-i-propylaminobutyl iodide, methylaminoethyl chloride, aminopropyl bromide, methylbenzylaminopentyl chloride, cyclohexylaminoethyl bromide, hydroxyethylaminohexyl iodide, hydroxyethoxyethylaminopropyl chloride, pyrrolidinoethyl chloride, piperidinopropyl iodide, piperazinobutyl chloride, morpholinopentyl bromide, thiamorpholinohexyl iodide as well as alkylene halides containing substituted heterocyclics as indicated hereinbefore.

Halocarbenes may be generated under basic conditions either by (a) reaction of haloform or ethyltrihaloacetate with a base like potassium hydroxide or potassium-t-butoxide; or (b) reaction of a polyhalide with an alkyl lithium. Halocarbenes may be generated under non-basic conditions by the decomposition of phenylhalomethylmercury.

Compounds of Formula I where R is hydrogen may be conveniently prepared from compounds of Formula I where R is benzyl, by hydrogenolysis using palladium on charcoal or other known catalyst for reduction.

The compounds of Formula I wherein the side chain has a basic amino function form physiologically acceptable acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Then any other salt may again be formed from the free base and the appropriate inorganic or organic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, phosphate, oxalate, tartrate, maleate, fumarate, pamoate, citrate, succinate, benzoate, ascorbate, methane-sulfonate, benzenesulfonte, toluenesulfonate, and the like.

The compounds of this invention can be utilized as parasiticides and rodenticides, being particularly useful against Hymenolepz's nana, Nematospiroides dubius, Nippostrongylus brasiliensis and Ascaris lumbricoides. These compounds when utilized as parasiticides form the active ingredient in feedstuffs for cattle, hogs and chickens, being admixed with said feed stock in from 0.1 to 25 mg. per 100 kg. weight of feed stuffs with the most preferred range being from about 5 to mg. per kg. of feedstuffs.

As anti-inflammatory agents, the compounds of this invention may be used topically and/ or orally in lieu of and in the same manner as cortisone in the treatment of acute inflammatory and allergic conditions of the eye, skin or mucose, e.g., as suspension, ointment or creme containing about 0.1 to about 2.5% by weight, of a compound of Formula I or physiologically acceptable salt thereof. In the rabbit or cow, for example, a 1% ointment is applied to the skin area 3 to 4 times daily.

Furthermore, the new compounds of Formula I are useful as antimicrobial agents and may be used to combat infections in animal species, such as mice, rats, dogs, guinea pigs and the like, due to organisms such as Trichomonas vaginalis, Trichomonas foetus, Staphylococcus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, Proteus vulgaris, Escherichia coli, C. albicans or Trichophyton mentagrophytes. For example, a compound or mixture of compounds of Formula I or physiologically acceptable acid addition salts as defined hereinbefore may be administered orally to an infected animal, e.g., to a mouse, in an amount of about 5 to 25 mg. per day in 2 to 4 divided doses. These may be conventionally formulated in a tablet, capsule or elixir containing about 10 to 250 mg. per dosage unit, by compounding the active substance or substances with the conventional excipient, vehicle, binder, preservative, flavor, etc., as called for by accepted pharmaceutical practice. They may also be applied topically, e.g., to dermatophytosis in a guinea pig, in a lotion, salve or cream at a concentration of about 0.01 to 3 percent by weight.

They may also be used as surface disinfectants. About 0.01 to 1 percent by weight of any of these substances may be dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. They may be incorporated also, for example, in a soap or other cleansing agent, e.g., a solid or liquid detergent, detergent composition, for example, in general cleaning, in cleaning dairy barns or equipment or cleaning food handling or processing equipment.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale.

8 EXAMPLE 1 3-(benzyloxy)-1,l-dichloro-1a,2,7,7a-tetrahydrolH-cyclopropa[b]naphthalene (A) 5,8 dihydro 1 naphthol.A 3-1. three-necked flask, equipped with a Dry Ice condenser, a sealed Hershberg-type stirrer, and an inlet tube is set up in a hood and charged with 108 g. (0.75 mole) of l-naphthol. The stirrer is started and to the rapidly stirred flask contents is added 1 l. of liquid ammonia as rapidly as possible (about 5 minutes). When the naphthol has gone into solution (about 10 minutes), 20.8 g. (3.0 g. atoms) of lithium metal is added in small pieces and at such a rate as to prevent the ammonia from refluxing too violently. After the addition of the lithium has been completed (about 45 minutes), the solution is stirred for an additional 20 minutes and is then treated with 170 ml. (3.0 moles) of absolute ethanol which is added dropwise over a period of 30-45 minutes. The condenser is removed, stirring is continued, and the ammonia is evaporated in a stream of air introduced through the inlet tube. The residue is dissolved in 1 l. of water, and after the solution has been extracted with two ml. portions of ether, it is carefully acidified with concentrated hydrochloric acid. The product formed is taken into ether with three 250 ml. extracts, and then the ether extract is washed with water and dried over anhydrous sodium sulfate. The ether is removed by evaporation to yield 106-108 g. (97-99%) of crude 5,8- dihydro-l-naphthol, M.P. 6971. This material is dissolved in benzene, treated with charcoal, concentrated and crystallized to give pure 5,8-dihydro-1-naphthol, M.P. 70.5-72".

(B) 5,8 dihydro-l-naphthol, benzyl ether.-Method 1): A mixture of 29.2 g. (0.2 mole) of 5,8-dihydro-1- naphthol, 28.0 g. (0.2 mole) of anhydrous K CO 37.69 g. (0.22 mole) of benzyl bromide and 200 ml. of dry acetone is stirred and refluxed for 12 hours. The solvent is removed in vacuo, the residue is mixed with 200 ml. of water, and extracted with ether. The ether extract is washed with water, dried (MgSO and evaporated to give 40 g. of oil, which solidifies on standing. A sample crystallized from pentane, melts at 69-72".

Analysis.-Calcd. for C H O (percent): C, 86.40; H, 6.83. Found (percent): C, 86.55; H, 6.75.

Method (2): To a cooled solution of 21.9 g. (0.15 mole) of 5,8-dihydro-1-naphthol in 100 ml. of anhydrous ethanol, 7.29 g. (0.15 mole) of 50% sodium hydride is added in portions. After the evolution of hydrogen has ceased, 25.6 g. (0.15 mole) of benzyl bromide is added dropwise, and the mixture refluxed with stirring for 12 hours. The solvent is removed in vacuo, the residue is mixed with 200 ml. of water and extracted with chloroform..The chloroform extract is washed with water, dried (MgSO and evaporated to give 33.5 g. (94%) of brown solid. It is dissolved in ether-pentane, decolorized with Darco, dried (MgSO and evaporated to give 30 g. of product, identical to that obtained by method (1).

(C) 3 (benzyloxy)-1,l-dichloro-1a,2,7,7a-tetrahydrolH-cyclopropa[b]naphthalene.-Method (1): A solution of 10 g. (0.042 m.) of benzyl ether of dihydro naphthol, in ml. of benzene and 11 g. of potassium t-butoxide are placed in a three-necked flask equipped with a N inlet, dropping funnel and magnetic stirrer. The flask is cooled in an ice bath while 11.8 g. of CHCl is added dropwise; the mixture turns dark. The temperature is maintained at about 25. After the addition, the mixture is stirred /2 hour at room temperature. Then water is added to quench the reaction. The product is extracted with ether-benzene mixture, the organic extract is washed with water, dried (MgSO and evaporated to give 13.8 g. of a dark oily solid. The solid is dissolved in MeOI-I, decolorized with Darco and filtered. On cooling 2.8 g. of crystals are obtained, M.P. 74-80". Recrystallization from methanol gives yellow crystals, M.P. 82-85, '1- CDCI 9 singlet at 4.931- (CH, of benzyl), 2.58-3.41- (aromatic protons).

Analysis.Calcd. for C H OC1 (percent): C, 67.73; H, 5.06; C1, 22.22. Found (percent): C, 67.78; H, 5.24; CI, 22.13.

Method (2): To a solution of 2.3 g. (0.01 mole) of benzyl ether of dihydronaphthol in 300 ml. of dry benzene, 3.9 g. (0.01 mole) of phenyl (trichloromethyl)mercuryis added, and the mixture refluxed for 48 hours. The precipitate '(phenylmercuric chloride) is filtered oif, and the solution concd. to give a solid residue. The solid is dissolved in methanol and allowed to crystallize slowly, 0.7 g., M.P. 82-85, IR identical to the product obtained by method (1).

EXAMPLE 2 1,1-dichloro-1a,2,7,7a-tetrahydro-lH-cyclopropa[b] naphthalen-3-ol A solution of 2 g. (0.006 m.) of product of Example 1 in 200 ml. of 95% ethanol and a slurry of 1 g. of Pd/C in 10 ml. of 95% are placed in a Parr bottle and hydrogenated until the uptake of hydrogen ceases. The catalyst is filtered off, the solvent is evaporated in vacuo, CHCl is added, dried (MgSO and solvent evaporated 10 1- CDCI singlet at 5.251 OH, 2.8-3.6-aromatic protons.

Analysis.-Calcd. for C H OCl (percent): C, 57.67; H, 4.40; Cl, 30.95. Found (percent): C, 57.72; H, 4.47; Cl, 30.73.

- EXAMPLE 3 3-[2-(dimethylamino)ethoxy]-1,1-dichloro-1a,2,7,7atetrahydro-lH-cyclopropa[b]naphthalene To a cooled solution of 2.3 g. (0.01 mole) of product of Example 2 in ml. of anhydrous ethanol 0.48 g. (0.01 mole) of 50% sodium hydride is added in portions. After the evolution of hydrogen has ceased, 1.5 g. (0.01 mole) of 2-dimethylamino) ethyl bromide is added dropwise, and the mixture is refluxed with stirring for 3 hours. The solvent is removed in vacuo, the residue is mixed with 25 ml. of water and the mixture extracted with chloroform. The chloroform extract is washed with water, dried (MgSO and concd. to give 3 [2 (dimethylamino) ethoxy] 1,1 dichloro 1a,2,7,7a-tetrahydro-1H-cyclopropa[b]naphthalene.

EXAMPLES 4-21 In a manner similar to that described in Examples 1,

in vacuo to give 1.3 g. f solid, M.P. 89--93 25 2 and 3, where the naphthol, halide (R X) and halocar- Recrystallization from hexane gives crystals, M.P. 92.5- bene employ are as Shown in columns 1, 2 and 3 respec tively, of Table I below, the product shown in column 4 W3 3450 cm." broad OH is obtained.

TABLE I Column 1 Column 2 Column 3 mx :CR R

Example R X R R R R R R R- IIEUIR 4 H 01 (MRI Br Br H Same as in 301111111515 1, 5 H 02H. 02H; Br H Br 01 11 iii). 6 H OCH: H 1 (CH2): 01 H H Do.

7 H OCzHs H 01 CH; 01 01 H Do.

(CH2):N

8 2-C3HI H H I CHzCOzCaHs Br H 4-C H1 Do. 9 3-C2Hu CH: H 31 CH: Bl. Br fi-CzHu D0.

10 4-0 CaHs H H C1 C1 G] 6-00 H D (emu-N N-om 2 11 H H H Cl CzHaOH Br Br H Do.

(CHz)z-N CiHlOH 12 H H H C] CHzCHzOOaH C1 01 H Do.

13 C4Ho C|Ho Bl C1 C1 D0.

14. H i-C H1 Cl H 01 a Q 15 4 S I 004130 H I 02H: Br 01 s D0.

2)a-N CH:

16 H H H Cl Cl Br H Do.

17 2-0 H CH 00H C1 Br 01 4-0 H D 6 ll I ll (CH2)I N 5 l1 0 18 3-OO5H11 H 01H" Br Br 01 5-0 6 H Do.

TABLE I-Continued Column 2 Column 3 Column 4 OR: f \/z\/3\ d l J R X :CR3R4 R Example R x R R R R R R R R R 19 4-0111" :111 02H. Cl 01 01 6431111; Do.

(CH:)1-N NH 220 Z-OCzHu OCzHs 003E; Bl 04H B1 C1 4-OCzH5 D0.

(CH2)s-N 1 H H H I 0 Cl H H Do.

(CHzh OCflIo What is claimed is: 2. Compounds in accordance with claim 1 wherein R 1. Compounds of the structure is lower alkyl.

3. Compounds in accordance with claim 1 wherein R 1 is aralkyl. R3 4. The compound in accordance with claim 1 having the name 3-(benzyloxy)-1,l-dichloro-1a,2,7,7a-tetrahy- 4 3 dro-1-H-cyclopropa[b]naphthalene.

References Cited UNITED STATES PATENTS 3,442,640 5/1969 Wood et al 260612 D X BERNARD HELFIN, Primary Examiner US. Cl. X.R.

260-612 D, 613 D, 613 R, 623 R GSBZa Data March Venkaachala L;

Narayanan the bc'nre-idanti I i-acted as s fiad patent low:

noun me EEG my no rmuia under Example 23,- d'elete the number 2.

portio n of th reading should Column 11, under-Exaanpl 20, "l" Should read 21 v Signed and sealed this l0th dayof September 1974.

fittest: I

MCCOY GIBSON, JR. (3]. MARSHALL DANN Commissioner of Patents 

